This project relates to the hypothesis that rheumatoid arthritis is a metabolic disease in which a low blood histidine is responsible for joint inflammation by permitting the physical-chemical conversion, by denaturation, of synovial fluid gamma globulin to aggregates which are inflammatory and antigenic (rheumatoid factors being the antibodies). This hypothesis is supported by the finding of hypohistidinemia in rheumatoid arthritis; the in vitro inhibition of the heat aggregation of human gamma globulin by histidine, penicillamine, and gold thiomalate; the augmentation of the thermal aggregation of human gamma globulin by hyaluronic acid; the evidence from two studies, one single-blind and the other double-blind, that oral L-histidine is effective and safe in the treatment of rheumatoid arthritis; and the finding that oral L-histidine decreases the titer of rheumatoid factor. It is our intention to study further the chemical mechanisms causing aggregation of human gamma globulin (e.g. disulfide fission and the sulfhydryl-disulfide interchange reaction) particularly with respect to the augmenting effects of hyaluronic acid, copper, and mechanical shearing and with respect to the inhibitory effects of gold compounds and L-histidine. Further clinical trials of L-histidine in rheumatoid arthritis, particularly in children and on the anemia of the disease, are planned.